Patients with chronic diseases such as cancer or infections often exhibit decreased or a loss of appetite (anorexia) which over a prolonged period of time leads to cachexia, a condition in which the patient loses fat and skeletal muscle mass and which is often accompanied by inflammatory conditions. Cachexia has been increasingly recognized as an independent risk factor for morbidity and mortality.
Conventional treatment for cachexia includes diet modification, and pharmacotherapy for which a number of drugs may be used, including corticosteroids such as prednisolone, progestational agents such as megestrol acetate and medroxyprogesterone acetate, and serotonin antagonists such as cyproheptadine (see in this regard, for example, Cancer Medicine 6, Table 144-2 “Pharmacologic Treatment of Cancer Cachexia”). However, such treatments are less than ideal as these drugs have known side effects which may be of particular concern in patients exhibiting cachexia as a result of a chronic condition which may be exacerbated by such side effects. As such, there is a continuing need to develop new therapeutics for use in the treatment of cachexia and related conditions.
In this regard, the human melanocortin-4 receptor (“MC4-R”), which is part of a central appetite reducing (anorexigenic) pathway, has been a target of research interest, as patients suffering from such chronic diseases typically exhibit increased cytokine production which activates the MCR4-R, leading to anorexia and eventually cachexia. For example, PCT Patent Application Publication No. 97/47316 discloses drug screening assays for identifying therapeutics useful in treating body weight disorders based on the MC4-R.
MC4-R is a G-protein coupled receptor (GPCR) which has been shown to be expressed primarily in the brain (Gantt et al., 1993, J. Biol. Chem. 268:15174-15179; Mountjoy et al., 1994, Mol. Endo. 8:1298-1308) and is known to play a crucial role in energy balance (Cowley, M A, Eur. J. Pharmacol. 480:3-11, 2003; Elies, R. et al. Eur. J. Biochem. 251:659-666, 1998). The sequences of the MC4-R in various organisms have been reported in the literature. In this regard, see for example European Patent Application No. 1167386 (canine and feline sequences) and U.S. Pat. Nos. 5,703,220 and 6,117,975 (human sequences).
Non-antibody compounds that affect the activity of the MC4-R have been reported (see in this regard, for example, U.S. Pat. No. 7,169,777, U.S. Patent Publication No. 2004/0082779, European Patent Application No. 1167386 and PCT Publication Nos. WO 01/085930 and 98/10068). Moreover, polyclonal antibodies have been generated against the MC4-R (Peter et al., Am. J. Physiol. Re ug 1. Integr. Comp. Physiol. 292:R2151-R2158, 2007), however monoclonal antibodies against the MC4-R have not been reported.
Accordingly, there exist needs in the art to develop new and improved therapeutic agents for the treatment of cachexia and related conditions, including the development of therapeutic agents, and in particular monoclonal antibodies, that modulate MC4-R activity. It is to these needs that the present invention is directed.